Sickle-cell disease (SCD) is a genetic blood disorder that is characterized by the presence of sickle-shaped red blood cells. These sickled cells clog small capillaries, leading to severe pain and organ damage [2]. The disease is the result of a single point mutation in the gene coding for the -chain of hemoglobin (Hb), leading to the incorporation of a valine surface residue in place of glutamic acid [1]. Under low oxygen conditions, a binding surface for the valine residue is revealed at the EF-helix interface also on the -chain. An intermolecular interaction occurs leading to polymerization of deoxygenated sickle-cell hemoglobin (HbS) and the characteristic sickling of the red blood cells (RBCs) [1]. Despite the fact that the molecular mechanism of SCD is well understood, no effective treatment exists [4]. Therefore, the discovery of molecules capable of preventing HbS polymerization would be highly desirable. Peptides and peptidomimetics have proven to be powerful tools for the manipulation of biological systems in a number of different contexts. Most relevant is their ability to bind to protein surfaces and disrupt key protein interactions [18-20, 30]. Several techniques are currently available for the discovery of peptidic and peptidomimetic compounds capable of serving as protein ligands [14,15]. The research plan for the development of novel therapeutics for sickle cell disease is three-fold. (1) Several one-bead-one- compound solid-phase libraries will be screened against HbS. The libraries are designed to bind to HbS in a manner capable of leading to the disruption of the key contact sites that lead to HbS polymer formation. It is hypothesized that these molecules will disrupt HbS polymerization. (2) Phage display libraries will be screened against oxygenated HbS, leading to the discovery of molecules that stabilize oxyhemoglobin, thereby preventing fiber formation. (3) Characterization of the ligands by fluorescence spectroscopy and photo-crosslinking will provide valuable information on the important contacts and allow for the synthesis of more potent second-generation ligands. This work represents a novel approach for development of therapeutics for this disease and provides an ideal training ground for undergraduate students, both of which fit the objectives of the R15 funding mechanism. PUBLIC HEALTH RELEVANCE: Sickle cell disease affects nearly 100,000 people in the United States, yet an effective treatment does not yet exist. Because of its relative low occurrence, it has not garnered significant attention from the pharmaceutical industry. The research proposed is the first step in defining the feasibility of a new strategy for treating this disorder through the use of modern screening and selection techniques.